The triterpenes constitute a promising class of anti-HIV agents. In our previous studies, two classes of anti-HIV betulinic acid derivatives exhibit very different anti-HIV profiles. IC9564 (1) and DSB (2) are examples of these two classes of anti-HIV agents. The class I compounds are betulinic acid with various C-28 amide modifications. The represent for this type of compound, IC9564 (1), the statine analog of betulinic acid, was found to be active at the early stage of viral infection (Sun, I. C; Chen, C. H.; Kashiwada, Y.; Wu, J. H.; Wang, H. K.; and Lee, K. H. Anti-AIDS Agents 49. Synthesis, Anti-HIV, and Anti-Fusion Activities of IC9564 Analogues Based on Betulinic Acid. J. Med. Chem. 2002, 45, 4271–4275; Holz-Smith, S. L.; Sun, I. C.; Jin, L.; Matthews, T. J.; Lee, K. H.; and Chen, C. H. Role of human immunodeficiency virus (HIV) type 1 envelope in the anti-HIV activity of the betulinic acid derivative IC9564. Antimicrob. Agents Chemother. 2001, 45, 60–66).
The class II anti-HIV agents are 3-acyl derivatives of betulinic acid. As an example, 3-O-(3′,3′-dimethylsuccinyl)-betulinic acid (DSB, 2) was reported inhibiting HIV-1 maturation by interfering with HIV-1 P24/P2 processing, which results in a noninfectious HIV-1 particle (Kashiwada, Y.; Hashimoto, F.; Cosentino, L. M.; Chen, C. H.; Garrett, P. E.; and Lee, K. H. Betulinic Acid and Dihydrobetulinic Acid Derivatives as Potent Anti-HIV Agents. J. Med. Chem. 1996, 39, 1016–1017; Li, F.; Goila-gaur, R.; Salzwedel, K.; Kilgore, N. R.; Reddick, M.; Matallana, C.; Castillo, A.; Zoumplis, D.; Martin, D. E.; Orenstein, J. M.; Allaway, G. P.; Freed, E. O.; and Wild, C. T. PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 13555–13560).

Among many class I modified C-28 amide compounds, a relatively long C-28 amide side chain is the common structure feature for relative potent anti-HIV entry activity. Compounds devoid of the C-28 side chain are totally inactive against HIV-1 entry (Hashimoto, F.; Kashiwada, Y.; Cosentino, L. M.; Chen, C. H.; Garrett, P. E.; and Lee, K. H. Anti-AIDS agents 27. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives. Bioorg. Med. Chem. 1997, 5, 2133–2143). Replacing of the C28 amide group with methylene group or carboxyl ester led to activity loss (Evers, M.; Poujade, C.; Soler, F.; Ribeill, Y.; James, C.; Lelievre, Y.; Gueguen, J. C.; Reisdorf, D.; and Morize, I. Betulinic Acid Derivatives: A New Class of Human Immunodeficiency Virus Type 1 Specific Inhibitors with a New Mode of Action. J. Med. Chem. 1996, 39, 1056–1068).
On the other hand, modifications on other parts of the betulin ring system do not significantly change their anti-HIV fusion activity. Modification of the 3-hydroxyl group with variety of acyl moiety does not significantly alter the anti-HIV entry profiles either. For class II BA derivatives, the most potent derivatives isovaleryl contain either 3,3-dimethyl-succinyl or glutaryl moieties at C-3. Terminal carboxylic acid domain in C-3 side chain is also required for potent anti-HIV activity (Sun, I. C.; Wang, H. K.; Kashiwada, Y.; Shen, J. K.; Cosentino, L. M.; Chen, C. H.; Yang, L. M.; and Lee, K. H. Anti-AIDS Agents. 34. Synthesis and Structure-Activity Relationships of Betulin Derivatives as Anti-HIV Agents. J. Med. Chem. 1998, 41, 4648–4657).
It was recently reported that betulinic acid derivatives with both C-3 and C-28 side chains possessed both anti-fusion and anti-maturation activity (Li, F.; Goila-gaur, R.; Salzwedel, K.; Kilgore, N. R.; Reddick, M.; Matallana, C.; Castillo, A.; Zoumplis, D.; Martin, D. E.; Orenstein, J. M.; Allaway, G. P.; Freed, E. O.; and Wild, C. T. PA-457: A potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 13555–13560; Huang, L.; Yuan, X.; Aiken, C.; and Chen, C. H. Bi-functional anti-HIV-1 small molecules with two novel mechanisms of action. Antimicrob. Agents Chemother. in press). Our previous papers reported that moronic acid (3), isolated from Brazilian propolis, also exhibited significant anti-HIV activity (EC50<0.1 μg/mL, TI>186) in H9 lymphocyte (Ito, J.; Chang, F. R.; Wang, H. K.; Park, Y. K.; Ikegaki, M.; Kilgore, N.; and Lee, K. H. Anti-AIDS Agents. 48.Anti-HIV Activity of Moronic Acid Derivatives and the New Melliferone-Related Triterpenoid Isolated from Brazilian Propolis. J. Nat. Prod. 2001, 64, 1278–1281).